3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one, hereinafter also referred to as ivabradine, is a novel medication used for the symptomatic management of stable angina pectoris. It is marketed under the trade name Procoralan, Coralan in India, Australia or, such as in Italy, Corlentor and was also known as S-16257 during its development. Ivabradine acts by reducing the heart rate in a mechanism different from beta blockers and calcium channel blockers, two commonly prescribed antianginal drugs. It is classified as a cardiotonic agent. The chemical structure of the marketed form, ivabradine hydrochloride, is shown in formula (I):

The polymorphic form δ (hereinunder: delta) of ivabradine hydrochloride and a method for its production is disclosed in U.S. Pat. No. 7,384,932, and the polymorphic form δd (hereinunder: delta-d) of ivabradine hydrochloride is disclosed in U.S. Pat. No. 7,867,997. According to the teaching of these documents, the crystallization of ivabradine hydrochloride is carried out in the solvent acetonitrile, wherefrom, depending on the drying conditions, either polymorphic form delta or polymorphic form delta-d is obtained. Acetonitrile is a class 2 solvent, and its content in pharmaceutical products is limited to 410 ppm (ICH Steering Committee, Guideline for Residual Solvents, 17 Jul. 1997). Therefore, the polymorphic forms delta or delta-d obtainable by crystallization from acetonitrile are not optimal in that they contain residual ICH class 2 solvent to a certain extent.
WO 2008/146308 discloses a process for the preparation of a further polymorphic form of ivabradine hydrochloride, the alpha form. Three concrete possibilities are disclosed how this alpha form can be obtained. First, in example 7, ivabradine hydrochloride is prepared using the well-known solvent acetonitrile. According to this synthesis, a further solvent, ethyl acetate, is necessary to obtain the alpha form. Second, in example 8, the starting material is amorphous ivabradine hydrochloride which has to be prepared in an upstream stage wherein this amorphous form is combined with ethyl acetate as solvent. Third, in order to obtain the alpha form, a process is described which starts with a mandatory heating step according to which ivabradine hydrochloride is taken up in acetone and heated to reflux in order to obtain a clear solution; after this heating stage and an intermediate filtration step, acetone has to be distilled off, i.e. a further heating and concentration step is required.
Polymorphism is a phenomenon relating to the occurrence of different crystal forms for one molecule. Different polymorphs may possess distinct advantageous physical properties such as increased solubility, increased chemical stability, decreased hygroscopicity, increased bulk density, increased photostability, improved processability during formulation and the like. The forms delta and delta-d of ivabradine hydrochloride are valuable polymorphs for the use in pharmaceutical preparations. However, the literature is silent on specific formulations exhibiting suitable conditions for the formulation of forms delta and delta-d of ivabradine hydrochloride.
An object of the present invention was the provision of a novel process for the preparation of polymorphic forms delta and delta-d of ivabradine hydrochloride, in particular form delta. Due to the fact that these polymorphic forms represent valuable products, it was an object that upscaling of this process—in order to meet the needs of industrial-scale production—should be easily accomplishable. It was a further object that the novel process allows for the production of high-purity products which, in particular, should contain as low an amount of possibly harmful compounds as possible.
Surprisingly, it was found that a novel crystalline solvate of ivabradine hydrochloride allows for the realization of this process. It was found that in terms of the starting material from which this solvate can be produced, the novel process is extremely flexible.
Further, it was found that the reaction conditions necessary to produce said crystalline solvate are highly advantageous in terms of energy consumption in combination with the chemical nature of the solvent used.
Yet further, it was found that starting from the novel acetone solvate, in particular the polymorphic forms delta and delta-d of ivabradine hydrochloride can be prepared in a simple and straightforward manner and that these polymorphic forms obtainable via the novel acetone solvate of the present invention are advantageous in that they are free of ICH class 2 solvents.